The experiments described in this proposal are designed to further our understanding of the biology of transposable elements and the molecular bases underlying their interaction with the genome of the host. In particular, we propose to study the gypsy retrotransposon and the mechanisms by which ifs insertion into various genes results in phenotypes that can be suppressed or enhanced by second site mutations at various modifier loci. Two of these loci, su(Hw) and mod(mdg4), appear to have parallel or complementary roles in the generation of these phenotypes. In addition to their effect on gypsy, the proteins encoded by these two genes may play important roles in general aspects of the control of gene expression in Drosophila. The role of the su(Hw) product will be investigated by examining domains of the protein involved in various aspects of its function both in the generation of gypsy-induced phenotypes and in normal development. In addition, putative genes whose expression is affected by this protein win be identified and analyzed. Other factors acting in conjunction with su (Hw) will be isolated by genetic and biochemical means, and further characterized. One of these putative factors might be encoded by the mod(mdg4) locus, which appears to belong to a family of structurally related proteins. The mod(mdg4) gene as well as other members of the family will be cloned and characterized. The analysis of the structure of the proteins encoded by these genes and their putative interactions with su(Hw), will increase our understanding of their mechanism of action and the basis of their effect on the phenotype of gypsy-induced mutations. These experiments may allow the characterization of a network of proteins that play general and fundamental roles in the expression of cellular genes and for which biochemical assays are unavailable. Finally, experiments will be carried out to determine the molecular bases of the control of retrotransposon mobilization in the Drosophila genome by examining various aspects of gypsy expression at which this control could be exerted.